Pathway selectivity in Frizzleds is achieved by conserved micro-switches defining pathway-determining, active conformations
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Pathway selectivity in Frizzleds is achieved by conserved micro-switches defining pathway-determining, active conformations. / Grätz, Lukas; Kowalski-Jahn, Maria; Scharf, Magdalena M.; Kozielewicz, Pawel; Jahn, Michael; Bous, Julien; Lambert, Nevin A.; Gloriam, David E.; Schulte, Gunnar.
In: Nature Communications, Vol. 14, No. 1, 4573, 2023.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Pathway selectivity in Frizzleds is achieved by conserved micro-switches defining pathway-determining, active conformations
AU - Grätz, Lukas
AU - Kowalski-Jahn, Maria
AU - Scharf, Magdalena M.
AU - Kozielewicz, Pawel
AU - Jahn, Michael
AU - Bous, Julien
AU - Lambert, Nevin A.
AU - Gloriam, David E.
AU - Schulte, Gunnar
N1 - Publisher Copyright: © 2023, The Author(s).
PY - 2023
Y1 - 2023
N2 - The class Frizzled of G protein-coupled receptors (GPCRs), consisting of ten Frizzled (FZD1-10) paralogs and Smoothened, remains one of the most enigmatic GPCR families. This class mediates signaling predominantly through Disheveled (DVL) or heterotrimeric G proteins. However, the mechanisms underlying pathway selection are elusive. Here we employ a structure-driven mutagenesis approach in combination with an extensive panel of functional signaling readouts to investigate the importance of conserved state-stabilizing residues in FZD5 for signal specification. Similar data were obtained for FZD4 and FZD10 suggesting that our findings can be extrapolated to other members of the FZD family. Comparative molecular dynamics simulations of wild type and selected FZD5 mutants further support the concept that distinct conformational changes in FZDs specify the signal outcome. In conclusion, we find that FZD5 and FZDs in general prefer coupling to DVL rather than heterotrimeric G proteins and that distinct active state micro-switches in the receptor are essential for pathway selection arguing for conformational changes in the receptor protein defining transducer selectivity.
AB - The class Frizzled of G protein-coupled receptors (GPCRs), consisting of ten Frizzled (FZD1-10) paralogs and Smoothened, remains one of the most enigmatic GPCR families. This class mediates signaling predominantly through Disheveled (DVL) or heterotrimeric G proteins. However, the mechanisms underlying pathway selection are elusive. Here we employ a structure-driven mutagenesis approach in combination with an extensive panel of functional signaling readouts to investigate the importance of conserved state-stabilizing residues in FZD5 for signal specification. Similar data were obtained for FZD4 and FZD10 suggesting that our findings can be extrapolated to other members of the FZD family. Comparative molecular dynamics simulations of wild type and selected FZD5 mutants further support the concept that distinct conformational changes in FZDs specify the signal outcome. In conclusion, we find that FZD5 and FZDs in general prefer coupling to DVL rather than heterotrimeric G proteins and that distinct active state micro-switches in the receptor are essential for pathway selection arguing for conformational changes in the receptor protein defining transducer selectivity.
U2 - 10.1038/s41467-023-40213-0
DO - 10.1038/s41467-023-40213-0
M3 - Journal article
C2 - 37516754
AN - SCOPUS:85165942213
VL - 14
JO - Nature Communications
JF - Nature Communications
SN - 2041-1723
IS - 1
M1 - 4573
ER -
ID: 366506795